Preservation of brain health is a critical goal in the care of adults with type 2 diabetes mellitus, who are at increased risk for atrophy, cerebrovascular disease, and cognitive impairment. Weight loss and increased physical activity hold promise as potentially effective strategies for this purpose, but are currently unproven in any population. Because unintended weight loss often precedes declines in later life brain health, a randomized controlled clinical trial is necessary, which must feature an effective behavioral intervention that is sustained over a long period of time in a large well characterized cohort. Mounting such a program de novo would be very expensive. Instead, we propose to make use of the ongoing and very successful Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, adding cross-sectional magnetic resonance imaging (MRI) to its extensive data collection protocol. This is feasible: participants in clinical trials have been repeatedly shown to be willing to join brain imaging studies and we have developed successful protocols for maintaining safety, confidentiality, and quality. This is novel: Look AHEAD and the state-of-the-art MRI protocols that we propose provide an unprecedented opportunity to assess the long-term effectiveness of mid-life behavioral changes on brain structure and function and to advance understanding of brain health in diabetes. We address an important public health priority for a rapidly growing and under-studied segment of the US population in a cost-effective manner, leveraging the extensive research resources available from Look AHEAD. We respond to PAR-09-247, which targets ancillary study applications to major NIDDK clinical trials, including Look AHEAD. We will enroll 496 participants, ages 55-85 years with type 2 diabetes, from 3 Look AHEAD clinics. They will have been randomly assigned 10 years ago when they were obese or overweight, with equal probability, to either an ongoing intensive lifestyle intervention that has induced sustained weight loss and increased physical activity or control condition (diabetes support and education) that has fostered excellent retention. A proven protocol for standardized structural MRI will provide regional brain and ischemic lesion volumes;functional MRI will provide assessments of functional activation, resting state connectivity, and cerebral blood flow. A tested cognitive battery and physical activity assessment will be administered. A comprehensive analysis of these data will make use of established statistical approaches and novel machine-learning methods. Look AHEAD provides extensive 10-year characterizations of participant's health and behavior, their medical care and its cost, and the trial's interventions;state-of-the art data management systems;and provisions for developing public access databases. Our research team includes established and productive experts in brain imaging, diabetes research, behavioral medicine, data and image analysis, neuroepidemiology, and collaboration.